Investigating the impact of genetic variation on ER stress response and disease

项目总结 治疗疾病的最大挑战之一是携带相同病毒的人 致病突变可能会导致不同的疾病结果。越来越多的人认识到 这种变异在很大程度上是由于每个人的遗传背景差异造成的。 在某些情况下，这种遗传变异似乎比潜在的病因更重要。 突变。为了真正了解基因变异如何与致病因素相互作用 突变，实验室疾病研究需要考虑到遗传变异。我们正在申请 这种方法可以应对内质网(ER)的应激反应。内质网是一个很大的细胞器 负责蛋白质的合成、成熟和传递，负责各种 基本功能。当错误折叠的蛋白质在内腔中积累时，就会发生内质网应激 呃。如果不加以解决，就会发生细胞死亡，随后就会发生疾病。细胞对内质网应激的反应是 未折叠蛋白反应(UPR)。UPR启动了一个非常大的转录反应， 旨在从内质网中清除错误折叠的蛋白质。ER压力是一个重要的组成部分 一些常见病和罕见病，包括糖尿病和神经退行性疾病。 重要的是，许多研究现在表明，药物或基因改造 内质网应激反应可以改变许多疾病的结局。我们假设基因 内质网应激反应的变化是疾病可变性的重要因素。为了 测试这一点，我们需要了解内质网应激在不同国家之间的性质和机制 个人。我们在小鼠和果蝇身上使用了许多工具来了解基因的作用 变种。我们最近证明了内质网应激反应和疾病的结局 内质网应激反应在不同的个体和基因之间是令人难以置信的可变和复杂的 背景。我们的长期目标是了解基因和基因变异如何相互作用 产生这样一种可变的反应。为此，我们将在本提案中重点关注两个方面：1) 揭示内质网应激反应遗传变异背后的遗传结构 老鼠。我们提出了一些研究，目的是在全基因组水平上理解这一点， 基因水平和SNP水平；以及2)了解遗传修饰物如何影响表型 内质网应激反应的疾病结局。了解基因变异如何影响一个关键的 与疾病相关的途径，如内质网应激，将有助于设计个性化的治疗方法 可能会更好地治疗个别病人。

PROJECT SUMMARY One of the biggest challenges to treating disease is the fact that individuals carrying the same pathogenic mutation can present with different disease outcomes. It is increasingly recognized that this variation can arise, in large part, due to genetic background differences of each individual. In some cases, this genetic variation appears to be more important than the underlying causative mutation. In order to truly understand how genetic variation interacts with disease causing mutations, laboratory disease studies need to take into account genetic variation. We are applying this approach to the endoplasmic reticulum (ER) stress response. The ER is a large organelle responsible for the synthesis, maturation, and delivery of proteins responsible for a variety of essential functions. ER stress occurs when misfolded proteins accumulate in the lumen of the ER. If left unresolved, cell death occurs, followed by disease. The cell responds to ER stress with the unfolded protein response (UPR). The UPR initiates a very large transcriptional response that is aimed at clearing misfolded proteins from the ER. ER stress is an important component to a number of common and rare diseases, including diabetes and neurodegenerative disorders. Importantly, many studies are now showing that pharmacological or genetic modification of the ER stress response can alter the outcome of many diseases. We hypothesize that genetic variation in the ER stress response is an important contributor to variability in disease. In order to test this, we need to understand the nature and mechanism by which ER stress varies among individuals. We utilize a number of tools in mouse and Drosophila to understand the role of genetic variation. We have recently demonstrated that the ER stress response and outcomes of disease of the ER stress response are incredibly variable and complex across individuals and genetic backgrounds. Our long term goal is to understand how genes and genetic variants interact to produce such a variable response. To do this, we will focus on two areas in this proposal: 1) Uncover the genetic architecture underlying genetic variation of the ER stress response in the mouse. We propose a number of studies aimed at understanding this at the genome-wide level, gene level, and SNP level; and 2) understand how genetic modifiers influence the phenotypic outcome of diseases of the ER stress response. Knowing how genetic variation impacts a critical disease-relevant pathway, like ER stress, will assist in designing personalized therapies that might better treat the individual patient.